The overall goal of this research program is to determine whether kappa opioid receptor antagonists have the potential to be developed as rapidly acting antidepressants. There is a clear medical need for new drugs that would expand the options for treating comorbid depression and anxiety, especially for the substantial number of patients refractory to current medications. Kappa opioid receptors and their endogenous ligand dynorphin are thought to be involved in the production of dysphoria and depression accompanying exposure to stress. Kappa opioid receptor antagonists can produce antidepressant and anxiolytic effects in animal models, but the pharmacological profile of existing compounds make them unsuitable for clinical development. The proposed studies would evaluate the effects of two novel kappa opioid receptors, LY2456302 and LY2444295, as potential antidepressant and anxiolytic drugs using animal behavior tests. Studies will determine whether the kappa opioid receptor antagonists produce their effects more rapidly than established antidepressants and similar to ketamine on tests such as the forced swim test, novelty-induced hypophagia and on acutely reversing the effects of chronic mild stress on anhedonia and anxiety. The mechanism of action of kappa opioid receptor antagonists will be confirmed using mice with constitutive deletion of kappa opioid receptors. Additional studies will identify the neural circuitry involved in producing these behavioral effects. Taken together, these experiments will strengthen a basic foundation for considering the development of a novel kappa opioid receptor antagonists as rapid acting antidepressants for eventual therapy in treatment-resistant depression.